Pulmonary hypertension (PH) is a multifaceted disease characterized by high blood pressure in the lungs, a life-threatening complication with no cure but with ongoing research to develop better treatments. An important pathophysiological mechanism in PH is oxidative stress, which promotes abnormal vascular responses. Reactive oxygen species (ROS), such as superoxide (O2−), are potent activators of a variety of disease pathways. In blood vessels, changes in O2− levels impact vascular tone, inflammation, cell growth and apoptosis. Elevated ROS in hypoxic pulmonary arteries can contribute to the development of PH. Superoxide dismutases (SODs) are the major natural antioxidant defense systems against O2−, operating by catalyzing the dismutation of O2− into hydrogen peroxide (H2O2) and molecular oxygen (O2).
Strategies for treating PH using compounds such as SOD mimetics are of great interest. For example, metalloporphyrins, a class of catalytic antioxidants, can scavenge a wide range of ROS. SOD mimetics are potent metal ion chelators that mimic the dismutation of O2− and effectively block oxidative stress in vivo, including acute lung injury. However, SOD/catalase enzymes known in the art have only moderate efficacy due to two major limitations. First, pharmacokinetic studies of metalloporphyrins show that they are distributed only at moderate levels to the lungs and heart. Second, metalloporphyrins have short half-lives in living tissue.
Therefore, there remains a need in the art for methods and compounds for the treatment of pulmonary hypertension. In certain embodiments, these methods and compounds can prevent oxidative stress by scavenging free radicals and/or inhibiting the production of free radicals, such as reactive oxygen species. The present invention addresses this need.